Stroke is the leading cause of death in the United States. Cerebral ischemia contributes to more than 80% of the stoke cases. One of the intriguing features of neuronal injury following transient cerebral ischemia is the selective cell death. CA1 pyramidal neurons in the hippocampus and medium spiny (MS) neurons in the striatum die after ischemia whereas the interneurons in the same region remain intact. The objective of this proposal is to reveal a novel mechanism that contributes to the selective cell death following transient cerebral ischemia. Excitotoxicity is a major cause of neuronal death after ischemia. The difference in neuronal excitability between the ischemia-vulnerable and ischemia-resistant neurons might be responsible to the selective cell death. Potassium currents play important roles in regulating neuronal excitability and therefore might contribute to the selective cell death after ischemia. Recent studies have shown that the A-type potassium current is significantly increased in ischemia-resistant neurons after ischemia but remains unchanged in ischemia-vulnerable neurons. We hypothesize that the alteration of A-type potassium current contributes to selective neuronal damage after ischemia. Medium spiny neurons in the striatum die in 24 hr after transient global ischemia while the large aspiny interneurons survive the same insult. Using striatal neurons, the experiments in this proposal are designed to test this novel hypothesis of selective cell death after ischemia. The viability of MS neurons in culture after oxygen-glucose deprivation (OGD) will be compared between neurons with or without over- expression of A-type potassium channel subunits (Kv1.4 and Kv4.2). Furthermore, the viability of neurons after blocking the A-type potassium current with pharmacological agents will be compared with that of control ones after OGD. Then the viability of striatal neurons in animals after over-expression of Kv1.4 and Kv4.2 using adeno-associated virus technique will be compared with that of naove ones after ischemia. The neuronal damage after ischemia will also be compared between the wild-type and transgenic mice lacking Kv1.4 and Kv4.2 subunits after ischemia. The proposed experiments will establish the causal relation of A-type potassium current in selective cell death and reveal a novel mechanism of neuroprotection against ischemia. The results of these studies will provide a new direction for developing pharmaceutical agents, such as A-type potassium channel activator/opener, for patients suffered from cardiac arrest upon resuscitation. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health concerns because it investigate the mechanisms of brain damage after stroke. The results of these studies will help to develop treatments for stroke patients.